Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers

Abstract

Objective To determine the spectrum of antiviral antibodies in HIV-1-infected individuals in whom viral replication is spontaneously undetectable, termed HIV controllers (HICs). Design Multicenter French trial ANRS EP36 studying the viral control in HICs. Methods Neutralizing Antibody (nAb) activities (neutralization assay, competition with broadly reactive monoclonal antibodies, and reactivity against the viral MPER gp41 region), FcγR-mediated antiviral activities, antibody-dependent cell cytotoxicity (ADCC), as well as autoantibody levels, were quantified in plasma from 22 controllers and from viremic individuals. The levels of these different antibody responses and HIV-specific CD8 T cell responses quantified by enzyme-linked immunosorbent spot (ELISPOT) IFNγ assay were compared in each controller. Results The levels of antibody against the gp120 CD4 binding site, gp41, as well as Env epitopes near to the sites bound by broadly nAbs 2F5 and 1b12 were not different between HICs and viremic individuals. We did not find significant autoantibody levels in HICs. The magnitude and breadth of nAbs were heterogeneous in HICs but lower than in viremic individuals. The levels of nAbs using FcγR-mediated assay inhibition were similar in both groups. Regardless of the type of antibody tested, there was no correlation with HIV-specific CD8 T cell responses. ADCC was detectable in all controllers tested and was significantly higher than in viremic individuals (P <0.0002). Conclusion There was no single anti-HIV-1 antibody specificity that was a clear correlate of immunity in controllers. Rather, for most antibody types, controllers had the same or lower levels of nAbs than viremic individuals, with the possible exception of ADCC antibodies.

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

“…Potent ADCC Ab levels are associated with slower progression from HIV infection to AIDS (4). Indeed, some studies (4) demonstrated that HIV-infected elite controllers have heightened levels of Abs capable of mediating anti-HIV ADCC.…”

“…Interest in ADCC has been stimulated by a series of observations implying the involvement of this immune response in the control and prevention of HIV infection. The potential for involvement of ADCC in controlling HIV infection was suggested by observations that Abs capable of mediating ADCC occur at higher titers in HIV-infected elite controllers than in viremic individuals (4), that ADCC Abs in slow progressors (SPs) target a broader range of epitopes than do ADCC Abs from non-SPs (5), and that higher ADCC activity is retained in rhesus macaques with slowly progressing infections with SIV compared with macaques with rapidly progressing infections (6). Furthermore, the potential ability of ADCC to prevent HIV infection was demonstrated by elegant passive-transfer experiments performed in rhesus macaques.…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…The mechanism through which these antibodies contribute to HIV control is unknown, although it seems to be unrelated to direct neutralization. In general, HICs possess heterogeneous but low levels of neutralizing antibodies, suggesting that they are not a major determinant of virus control [134,175]. By contrast, rstb.royalsocietypublishing.org Phil.…”

“…R. Soc. B 369: 20130436 greater antibody-dependent cell-mediated cytotoxicity (ADCC) potential associated with both the quality of nonneutralizing antibodies and the levels of FCg receptors on the surface of effector cells has been observed in HICs [17,[175][176][177]. The induction of ADCC-mediating antibodies was observed in vaccinated volunteers in the RV144 vaccine trial [178], showing marginally significant protection from HIV infection [179] and further reinforcing the potential therapeutic utility of ADCC.…”

HIV/AIDS: 30 Years of progress and future challenges

“…This observation suggests that maintenance of NAbs requires virus expression. However, ECs and other LTSs may benefit from antibodydependent cellular cytotoxicity (ADCC) [73]. By this process, antiviral antibodies bind to infected cells that are killed by NK cells and neutrophils.…”